Abstract: Neurotrophic factors can induce and maintain differentiation and prevent naturally occurring and experimentally induced neuronal cell death. Therefore, these peptides are especially attractive agents for the treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). However, although much is known about the roles of neurotrophic factors in restoring cell phenotype following injury in the adult mammalian brain, the mechanisms whereby these peptides prevent neuronal cell death are less well understood. One difficulty in interpreting experiments designed to clarify this aspect of the biology of neurotrophic factors is the absence of definitive markers for dying neurons. The present proposal utilizes recently developed methods for labeling degenerating cells (the terminal transferase-mediated dUTP- biotin nick end labeling [TUNEL] staining method for nuclei and DNA laddering in Southern blots) to examine two well-characterized models of experimental degeneration of basal forebrain cholinergic and anterior thalamic neurons for evidence of neuronal death or programmed cell death. To assess the effects of neurotrophic factors in these models of neuronal cell deaths, we will damage the appropriate axon-specific paths (fimbria- fornix model and cingulatory model) and will examine NGF and CNTF respectively can reduce or eliminate TUNEL labeling or DNA laddering in dying neurons. In parallel studies, using tissues from individuals with AD or other neurodegenerative diseases, we will use TUNEL labeling and DNA laddering study the death of subsets of neurons, the existence of apoptic mechanisms and the progression of disease. Finally, in studies of axonal transport we will investigate further the mechanisms whereby signals are transduced by neurotrophins in the central nervous system. In concert, these studies will clarify critical issues relevant to neuronal cell death in the adult mammalian brain and the potential of neurotrophic factors as therapeutic agents to ameliorate death of neurons in human neurodegenerative diseases.